Significance of the proposed research. Diarrheal disease caused by enteric bacteria is an important endemic health threat and a major source of food borne disease. Enterohemorrhagic E. coli (EHEC) is especially important because it is the leading cause of pediatric renal failure in children and is commonly transmitted via contaminated beef and vegetable products. In spite of the appreciated magnitude of the threat to human health and economic burden caused by EHEC, we still do not fully understand how EHEC virulence proteins cause diarrhea by subverting the normal cellular functions of the host intestine. The specific aims of this project are to 1) Identify the EHEC effector protein responsible for reducing Nod2 abundance in intestinal epithelial cells and characterize the mechanism through which it acts, and 2) Characterize EHEC modulation of host mitogen-activated protein kinase (MAPK) and NF?B pathways. This project will be significant because it will identify and characterize how translocated EHEC effector proteins modulate host innate immune signaling pathways. These studies will have significant positive impact on the design of new strategies to combat diarrheal pathogens. PUBLIC HEALTH RELEVANCE: E. coli is a significant source of food borne disease, often resulting from ingestion of under-cooked beef products or contaminated vegetables. A new group of E. coli proteins has been discovered that is likely to contribute to diarrheal disease by disrupting the ability of the host immune system to respond to infection. The applicant is characterizing the biological activities of these proteins with the goal of developing new therapeutic strategies for E. coli and related diarrheal pathogens.